The central objective of our Program Project Grant Signaling Processes Underlying Cardiovascular Function, is to extend our investigation of integrating specific signaling pathways underlying cardiac function to normal and pathogenic fibrosis. The central hypothesis is that the signaling pathways centered in the fibroblast are critical to the fibrotic processes characteristic of so much cardiovascular disease and heart failure. There is truly a remarkable lack of data and understanding as to if and how fibroblasts themselves contribute to cardiac disease. The 3 Projects will direct their efforts at determining the exact identity of the signaling pathways within fibroblasts that mediate myofibroblast transformation and longstanding fibrosis in surgically, pharmacologically- and genetically-induced cardiac disease. All of the Projects will also attempt to identify therapeutic windows for impacting favorably on the processes' pathogenic consequences. Our group consists of 3 Project Leaders and 4 Core-oriented investigators who have a track record of sustained and productive collaboration. The synergy and collaborations that underlie the PPG are underscored by the commonality of approach and the seamless use of models across the Projects. The goal of this Program is to prove proof-of-concept of fibroblast-based signaling pathways' importance in cardiac disease. Project 1's title is: Fibrotic signaling in cardiomyopathy. Jeffrey Robbins, Ph.D., Professor of Pediatrics, will focus on testing the central hypothesis that TGF signaling processes that are fibroblast-based play a critical role in the fibrotic response in sarcomere-based and nonsarcomere- based disease. Project 2's title is: Wnt/-catenin signaling and cardiac fibrosis. Katherine Yutzey, Ph.D., Professor of Pediatrics, will test the hypothesis that Wnt/-catenin signaling promotes normal development of interstitial fibroblasts and also contributes to pathologic interstitial fibrosis in adult cardiovascular disease. Project 3's title s: TGF signaling and its role in cardiac fibrosis. Jeffery Molkentin, PhD., Professor of Pediatrics, will focus on canonical and non-canonical TGF signaling in the cardiac fibroblast during cardiac disease development induced as a result of surgical intervention. The hypothesis is that the fibroblast responds to TGF and other cytokines through select signaling pathways in promoting fibrosis and maladaptive remodeling. These projects are supported by 3 Cores: Core A: The Administrative Core; Core B: The Physiology Core and Core C: The Imaging-Cell Culture Core. (End of Abstract)